This proposal describes a five year career development program aimed at providing the applicant with the requisite skills and background for an academic career as a clinician-scientist in neuroimmunology and neuromuscular disease. The principal investigator is currently a practicing academic neuromuscular physician and clinical researcher specializing in autoimmune myasthenia gravis (MG). He now proposes to shift his career course to supplement this clinical background with basic science research skills allowing for bench-to-bedside translation of clinically relevant laboratory discoveries. Supervised laboratory research will take place under the direction of Dr. Bellur Prabhakar, Chair of the Department of Microbiology and Immunology and a recognized leader in the field of immunology, who will mentor the principal investigator's scientific development. Dr. Premkumar Christadoss will serve as co-mentor, contributing his recognized expertise in experimental autoimmune myasthenia gravis (EAMG). Autoimmune MG is a prototypic antibody-mediated autoimmune disorder in which the target antigen, the skeletal muscle acetylcholine receptor (AChR) is well-characterized. MG is an ideal model of autoimmunity, and insights relevant to MG may be applied to other autoimmune diseases. Research in this proposal will focus on studies examining immunoregulatory mechanisms in EAMG aimed at identifying clinically relevant antigen-specific treatment. Preliminary studies by the principal investigator have shown that treatment with the hematopoietic growth factor, GM-CSF, has a pronounced suppressive effect on the induction of EAMG. The proposed experiments will, therefore, examine the therapeutic potential of GM-CSF in treating established EAMG.
The Specific Aims i nclude: 1) Examination of the therapeutic potential of GM-CSF in EAMG and characterization of its effects on AChR-specific immune responses. 2) Exploration of the role of regulatory T cell subsets in the GM-CSF-induced suppression of EAMG, the mechanism of their effect and their role in the suppression of pathogenic anti-AChR antibody production. 3) Investigation of GM-CSF's local effects on immune molecules and other NMJ proteins in EAMG mice. These studies are expected to provide significant insights into the nature and mechanisms of the effects of GM-CSF-induced regulatory cells in EAMG and provide additional information regarding EAMG's immunopathogenesis.
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